Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase domain containing 1 (NAPRT1) are the main human NAD salvage enzymes. NAD regulates energy metabolism and cell signaling, and the enzymes that control NAD availability are linked to pathologies such as cancer and neurodegeneration. Here, we have screened normal and tumor samples from different tissues and populations of origin for mutations in human NAMPT and NAPRT1, and evaluated their potential pathogenicity. We have identified several novel polymorphisms and showed that NAPRT1 has a greater genetic diversity than NAMPT, where any alteration can have a greater functional impact. Some variants presented different frequencies between normal and tumor samples that were most likely related to their population of origin. The novel mutations described that affect protein structure or expression levels can be functionally relevant and should be considered in a disease context. Particularly, mutations that decrease NAPRT1 expression can predict the usefulness of Nicotinic Acid in tumor treatments with NAMPT inhibitors.